Interstitial cystitis (“IC”) is an idiopathic illness of visceral hypersensitivity characterized by increased urinary frequency/urgency and pelvic pain for which effective therapy, especially for those with long standing or severe symptoms, remains elusive. The variability in the presentation and comorbid illnesses, whether the primary symptom is pain or urinary frequency, as well as diversity of response to therapies, suggest that IC be viewed as a symptom complex resulting from a variety of separate underlying but potentially interrelated mechanisms rather than a disease with a uniform pathophysiology. There continues to be controversy as to whether the problem is a specific bladder process or a manifestation of a more systemic autoimmune/endocrine disease with regional pelvic visceral/somatic dysfunction.
The absence of an established uniform underlying (and measurable) pathophysiology results in difficulty defining IC and appropriate diagnostic criteria. IC was originally characterized by urinary symptoms and cystoscopic visualization of ulcerations of bladder mucosa. The number of patients diagnosed subsequently was broadened by inclusion of findings of submucosal petechial hemorrhages (glomerulations) following hydrodistension of the bladder under anesthesia. The International Continence Society has proposed the term Painful Bladder Syndrome for patients experiencing a similar symptom complex. It has been reported, however, that a number of IC patients may be excluded under this new definition (Warren et al., “Using the International Continence Society's definition of painful bladder syndrome,” Urology 67:1138-1142 (2006)). A test has been promoted for diagnosis utilizing intravesical instillation of concentrated potassium chloride and recording whether this elicits bladder discomfort (Parsons et al., “Prevalence of interstitial cystitis in young women,” Urology 64:866-870 (2004)). Both cystoscopy and the potassium sensitivity test are reported to have shortcomings in regard to sensitivity and specificity. The literature regarding hydrodistension is complicated by the lack of a consensus in protocol/methodology in performing the procedure, with a study revealing a wide variability in the practice (Turner et al., “How do you stretch a bladder? A survey of UK practice, a literature review, and a recommendation of a standard approach,” Neurourol Urodyn 24:74-76 (2005)). It has also been recently reported that the appearance of glomerulations is not constant and may develop over time (Shear et al., “Development of glomerulations in younger women with interstitial cystitis,” Urology 68:253-256 (2006)).
The spectrum of severity of symptoms and the difficulties encountered with hydrodistension and potassium sensitivity testing are such that biomarkers have been evaluated as an aid to diagnosis. The most comprehensive report compared a number of putative biomarkers in an IC population. While antiproliferative factor (“APF”) appeared to be the most specific for IC (Erickson et al., “A comparison of multiple urine markers for interstitial cystitis,” J Urol 167:2461-2469 (2002)), a reliable commercial assay for APF has yet to be developed and the control of its production and its role in actually causing symptoms remains uncertain. Although there is a trend to make a diagnosis based on symptoms and an office test such as intravesical potassium sensitivity, IC still remains a diagnosis of exclusion, and reasonable attempts should be made to find a correctable underlying etiology.
The etiology of IC is still uncertain and may consist of multiple coexisting and reinforcing mechanisms. Prevalent theories include possible infectious origin, bladder permeability defects, local neurogenic and histamine-induced inflammation, as well as a more generalized vulnerability to visceral hypersensitivity due to genetic or acquired abnormalities of the immune or neuroendocrine system.
Recent advances have demonstrated that the urothelium and its innervations are much more complex than previously thought, with a variety of interrelated pathways that may in part explain IC pathogenesis (Kanai et al., “Symposium report on urothelial dysfunction: pathophysiology and novel therapies” J. Urol. 175:1624-1629 (2006); Steers et al., “Mechanisms of disease: the role of nerve growth factor in the pathophysiology of bladder disorders,” Nat Clin Pract Urol 3:101-110 (2006)). IC bladders demonstrate abnormal secretion of APF, nerve growth factor, inflammatory cytokines, ATP and multiple other signaling molecules. Abnormal production of some of these substances can persist once cells are removed from the urinary environment and grown in culture (Ruggieri, “Mechanisms of disease: role of purinergic signaling in the pathophysiology of bladder dysfunction” Nat Clin Pract Urol 3:206-215 (2006); Sun et al., “Augmented extracellular ATP signaling in bladder urothelial cells from patients with interstitial cystitis” Am J Physiol Cell Physiol 290:C27-C34 (2006)). These abnormalities in cellular signaling have yet to be fully explored in regard to opportunities for diagnosis or treatment.
There is also increasing awareness in those treating IC that the pathology and abnormal physiology associated with IC may well extend outside the bladder, requiring a broader view of therapeutic targets. IC is a syndrome defined by bladder symptoms, but it has been appreciated that IC patients will often have an increased prevalence of certain comorbid illnesses including allergies, irritable bowel syndrome, and fibromyalgia. When compared with the general population, the incidence of inflammatory bowel disease was estimated to be about 30 times more common in IC patients who had ulcers than in the general population (Peeker et al., “Intercurrent autoimmune conditions in classic and nonulcer interstitial cystitis,” Scand J Urol Nephrol 37:60-63 (2003)). A study (Warren et al., “Prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis,” Urology 63:17-21 (2004)) evaluating possible genetic influences found a 17-fold greater prevalence of the disease in adult first degree relatives of women with IC, suggesting a genetic predisposition to a hypersensitivity syndrome. The effects of hormonal cycle have been documented in IC patients and reveal alterations of pain sensitivity and bladder functioning during the menstrual cycle. This suggests, therefore, the possibility of hormonal manipulation in patients so affected, but this has not been rigorously tested (Powell-Boone et al., “Menstrual cycle affects bladder pain sensation in subjects with interstitial cystitis,” J Urol 174:1832-1836 (2005)). Advances in the future treatment of IC will likely depend on finding methods to better identify subgroups of patients with improved likelihood of response to certain types of therapy.
The present invention is directed to overcoming these and other deficiencies in the art.